Conditioning composition

ABSTRACT

The present invention is directed to a composition for the conditioning of a dental mineralized surface and/or a dental implant and/or for increasing the hydrophilicity of a dental implant having a metal containing surface. The composition comprises EDTA in a concentration of about 21-55% by weight and hydrogen peroxide at a concentration of about 2-4% by weight. The composition of the invention may be used for the conditioning of mineralized dental surfaces and dental implant surfaces in order to remove e.g. biofilm, debris, bacteria, bacterial toxins etc and/or for increasing the hydrophilicity of an implant having a metal containing surface. The invention is also directed to a kit comprising the composition of the invention and a device to apply the composition to a surface in need of conditioning.

TECHNICAL FIELD

The present invention is within the field of compositions forconditioning of mineralized dental surfaces and/or dental implantsurfaces. In particular, the invention is directed to a compositioncomprising EDTA and hydrogen peroxide to be used for the removal of e.g.biofilm, bacteria, debris, bacterial toxins, tissue etc. from a dentalsurface and/or a dental implant surface and/or for increasing thehydrophilicity of a dental implant having a metal containing surface.More particularly, the invention is directed to the composition for usein treating disease such as periodontal disease, periimplantits, cariesand/or an infection and/or inflammation in the root canal.

BACKGROUND ART

Diseases affecting the oral cavity and the teeth and their supportingtissue are very common in adult humans. Such diseases can have a largeimpact on the individuals affected as they may cause pain, problems withchewing, tooth loss, bad breath etc. and even affect the whole body dueto inflammations causing systemic immune responses.

Periodontal disease is an oral disease affecting almost all adults. Itis a progressive disease having the serious consequence of leading topartial or complete tooth loss. Periodontal diseases affect the tissuesthat support and anchor the teeth. The tissues affected by periodontaldisease are the gums (including the gingival) periodontal ligament,cementum, and alveolar bone. If not treated, periodontal disease resultsin the destruction of the gums, alveolar bone, and the outer layer ofthe tooth root. The main area involved in periodontal disease is thegingival sulcus, a pocket between the teeth and the gums.

Periodontal disease may occur in different forms: gingivitis, acutenecrotizing ulcerative gingivitis, adult periodontitis, and localizedjuvenile periodontitis.

Gingivitis is an inflammation of the outermost soft tissue of the gumswhich become red and inflamed, loose their normal shape, and becomesprone to bleeding.

Periodontitis is a condition in which gingivitis has extended downaround the tooth and into the supporting bone structure. Anaerobicbacteria may grow in pockets between the gums and teeth formed by theaccumulation of plaque and tarter. When the bacteria reach the roots ofthe teeth, the bacteria further cause damage to the tooth supportingbone structure.

Adult periodontitis is the most serious form of the periodontaldiseases. It involves the gingiva, periodontal ligament, and alveolarbone, resulting in deep periodontal pockets forming between the teeth,the cementum, and the gums. Plaque, calculus, and debris from food andother sources collect in the pocket. If left untreated, the periodontalligament can be destroyed and resorption of the alveolar bone may occurallowing the teeth to move more freely and eventually be lost.

The risk of being afflicted by periodontal disease increases with ageand bad oral hygiene. The presence of certain species of bacteria inlarge enough numbers in the gingival pocket and related areas correlateswith the development of periodontal disease; removal of these bacteriacorrelates with reduction or elimination of disease.

Periodontal disease can usually be prevented by good dental hygiene,such as by tooth brushing and flossing. However, once tartar is formed,it has to be removed by a dentist. Also, treatment of periodontitisrequires professional dental care. The pockets around the teeth must becleaned, and all tartar and plaque removed, all the way down to the rootif this is also afflicted. Conventional treatment involves both surgicaland non-surgical procedures. Surgery may in particular be necessarywhere the pockets are very deep. Also, antibiotic treatment to removeinfectious bacteria may be necessary.

Normally, treatment starts by scraping (scaling and root planing) thetooth surfaces in order to remove both visible bacterial deposits anddental calculus and deposits hidden below the gingival margin. Thisreduces gingival swelling caused by inflammation and often reduces thedepth of the periodontal pockets. However, adequate scaling and rootplaning performed below the gingival margin is difficult and in deeperperiodontal pockets inaccessible infected sites will serve as reservoirsfor reinfection. Consequently, surgical procedures, which will enhanceaccess and visibility, may have to be used to completely eliminate softand hard bacterial deposits. During periodontal surgery, theperiodontitis-affected roots are exposed by detaching the gingiva fromthe roots and alveolar bone. The roots are then freed from bacterialdeposits and dental calculus by scaling and root planing. This involvesalso removal of granulation tissue and root cementum contaminated bybacterial toxins. After the area has been cleaned, the gingival flapsare repositioned and sutured.

Such conventional treatment procedures are conservative and will only,at best, preserve the remaining tooth supporting tissues. Thus, toothsupport that has already been lost cannot be recreated by conventionaltreatment.

Periodontal healing is a primary concern in the treatment of periodontaldisease. This is a process largely dependent on the tissue reactionstaking place at the hard/soft tissue interface on the root surface.Long-term studies on healing of periodontal wounds with marginalcommunication following periodontal treatment have indicated thatcellular colonization of the wounded area results from a competitionbetween alveolar bone, oral epithelium and mucosal connective tissue aswell as periodontal connective tissue.

Most often deep furcation involvements do not lend themselves tosuccessful periodontal healing with conventional periodontal surgery.

Etching during periodontal surgery is performed mainly with three aims:removal of bacterial toxins, removal of smear layer and exposure ofcollagenous fibres in the root surface and increase visibility throughhemostatic effects.

Of these, the two first have been evaluated in vitro employing mainlycitric acid and to some extent ortho-phosphoric acid both of whichoperate at a pH of around 1 (Lowenguth R A, Blieden T M. Periodontalregeneration: root surface demineralization. Periodontology 2000 1993;1:54).

Scaling and root planing is performed to remove bacterial deposits,calculus and the superficial layers of the root surface (cementum anddentin), structures and tissues which harbor bacterial toxins. Suchtoxins are not only confined to the bacterial deposits but are alsofound adsorbed to periodontally diseased root surfaces.

These substances have been shown to inhibit cell attachment in vitro, afunction necessary for healing. Thus, the aim of scaling and rootplaning is to provide a biologically acceptable surface for marginalhealing. However, following root surface instrumentation, areas ofcontaminated cementum, as well as a smear layer covering theinstrumented surfaces may still remain. Additional root surfacetreatment, such as etching has been reported to remove the smear layer.

Application of etching agents has been reported to remove smear anddebris which may result from scaling and root planing. However, it alsoaffects the mineralized root surface, although contradictory resultshave been reported depending on mode of application of the agent.

Burnishing the root surface with a cotton pellet soaked in citric acidappears to expose more intertubular fibrils and widen dentinal tubulesto a greater extent compared to simple application of a drop of the acidor by placing an acid-saturated cotton pellet on the root surfacewithout rubbing, although reports have also indicated no difference.

Several studies have studied periodontal healing following citric orortho-phosphoric acid etching of root surfaces exposed duringperiodontal surgery, while only few studies have evaluated surroundingsoft tissue reactions after acid application. A surprisingly small areaof the soft tissue around the site of application appears to suffer anydamage despite the low pH (around 1). However, more profound effects onperiodontal healing have been reported, although the results appearhighly variable.

Since its inception citric and ortho-phosphoric acid etching (pH 1) ofroot surfaces have been reported to result in new attachment orreattachment. Later these claims have been disputed, and most in vivostudies indicate that connective tissue healing with some reparativecementum formation will result rather than formation of a longepithelial junction. There is also reason to believe that application ofcitric or ortho-phosphoric acid to a periodontal wound during surgerywill increase visibility through hemostatic effects as well asfacilitate removal of granulation tissue.

WO96/09029 discloses a composition comprising EDTA for use forconditioning of a biological mineralized surface. The amount of EDTA ofthe composition of WO96/09029 is near or at saturation of the EDTA whenin an aqueous matrix, the saturation point for EDTA lying between 22 and27% by weight based on the water content of the composition. The pH ofthe composition is from 6 to 8, preferably around neutral pH of 7. Thiscomposition was demonstrated to selectively remove hydroxyapatite butnot the collagenous matrix of dentin, in contrast to ortho-phosphoricacid-based etching compositions.

Hydrogen peroxide (H₂O₂) is used as an antiseptic or a bleaching agentin many different applications, including medical applications as wellas for domestic purposes. In dental compositions hydrogen peroxide hasbeen used e.g. for its disinfecting properties and for bleaching teeth.

Restorative materials are widely used in the medical field. In thedental area, restorative materials such as amalgam or resin compositesare often used to repair dental tissues and bones, for example in thecase of dental caries or restoration of tooth injuries. However, inorder for such materials to be able to firmly attach to the tooth, thesurface of the tooth has to be clean and without adhering bacteria,calculus etc. Also in the case of root fillings, the tooth root canalhas to be cleaned and the pulp removed therefrom.

Dental implants are utilized in dental restoration procedures inpatients having lost one or more of their teeth. A dental implantcomprises a dental fixture, which is utilized as an artificial toothroot replacement. Thus, the dental fixture serves as a root for a newtooth. The dental fixture is typically a screw, i.e. it has the shape ofa screw, and it is typically made of titanium, a titanium alloy,zirconium or a zirconium alloy. The screw is surgically implanted intothe jawbone, whereafter the bone tissue grows around the screw and thescrew is fixated in the bone with the bone in close contact with theimplant surface. This process is called osseointegration, becauseosteoblasts grow on and into the surface of the implanted screw. Bymeans of the osseointegration, a rigid installation of the screw isobtained.

Once the implant screw is firmly anchored in the jawbone, it may beelongated by attachment of an abutment to the screw. The abutment may,just as the screw, be made of titanium, a titanium alloy, zirconium or azirconium alloy. The shape and size of the utilized abutment areadjusted such that it precisely reaches up through the mucosa afterattachment to the screw. A dental restoration such as a crown, bridge ordenture may then be attached to the abutment.

Alternatively, the implant screw has such a shape and size that itreaches up through the mucosa after implantation, whereby no abutment isneeded and a dental restoration such as a crown, bridge or denture maybe attached directly to the screw.

The surface of dental implants sometimes has to be cleaned afterplacing. This is particularly important when an infection orcontamination occurs, causing a progressive degenerative process in thebone adjacent to the implant known as periimplantitis. This is aninflammatory condition of the mucosa and/or bone around the implantwhich may result in bone loss and eventual loss of the implant.Currently there is no universal agreement on the best treatment forperi-implantitis. However, in periimplantitis it is important to cleanthe surface of the ailing implant from microbes and contaminants to stopthe progression of the disease and ensure re-integration of the implant.Failure to clean the implant surface will eventually lead to loss ofbone and implant, and make further alternative treatments difficult andsometimes even impossible. This cleaning may involve mechanical as wellas chemical treatment of the implant and the surrounding bone andtissue.

In conclusion, it is important in many aspects to be able to efficientlyclean the surface of a mineralized tissue or an implant. Also, there isa need for a composition allowing the cleaning of an implant surface inorder to enhance and/or enable osseointegration of the implant. Also,there is a need for a conditioning composition allowing for thetreatment of periimplantitis. Thus there is still a need in the fieldfor efficient compositions allowing for a sufficient conditioning of thesurface of a mineralized tissue or a medical implant in order to preventand/or treat diseases affecting the oral cavity, such as periodontaldisease and periimplantitis.

SUMMARY OF INVENTION

The object of the present invention is to provide compositions for theconditioning of mineralized dental surfaces and/or surfaces of dentalimplants and/or for increasing the hydrophilicity of a dental implanthaving a metal containing surface.

This object is achieved by the provision of a conditioning compositioncomprising ethylenediaminetetraacetic acid (EDTA) at a concentration inthe range of about 21-55% by weight and hydrogen peroxide at aconcentration of about 2-4% by weight. The pH of the composition rangesfrom 6 and above, in particular 6-11.5.

The EDTA in the composition provides a conditioning effect on dentalmineralized surfaces and/or dental implants e.g. removing biofilm, aswell as it may aid in dissolving proteins and/or removing biologicaldebris.

The combination of EDTA and hydrogen peroxide also provides the effectof increasing the hydrophilicity of a metal containing implant surfaceafter treatment with the composition of the invention markedly comparedto when EDTA or hydrogen peroxide are used alone. A high hydrophilicityof an implant surface is desirable e.g. as this has the effect ofaccelerating bone and soft tissue regrowth on and around the implant.When an implant surface is conditioned with a composition of theinvention the osseointegration of the implant may be enabled and/orenhanced.

Also, if a more basic pH of the composition is used, such as 9 or above,it has surprisingly been found that a higher amount of EDTA is dissolvedthan is possible when a lower pH is used. Thereby EDTA may be dissolvedabove its normal saturation point in compositions having a pH aroundneutral, even if the compositions contain the same total amount of EDTA.The conditioning composition is more effective in the conditioning ofmineralized dental surfaces and/or surfaces of dental implants. Forexample biofilm dissolution is increased. Also, the use of thecomposition of the invention has advantageous effects in the case ofperiimplantitis.

The present invention is therefore also directed to the use of aconditioning composition for the conditioning of a mineralized dentalsurface and/or a surface of a dental implant and/or for improving thehydrophilicity of an implant having a metal containing surface.

The invention is further directed to the conditioning composition foruse as a medicament, such as for use in the treatment of a periodontaldisease, periimplantitis, caries and/or an infection and/or inflammationin a root canal.

The invention is also directed to a kit comprising a vial with theconditioning composition and a device for the conditioning of amineralized dental surface and/or a surface of a dental implant.

DEFINITIONS

By “weight %”, “% by weight”, “wt %” and the like is in the presentcontext meant the amount of a solute (by weight) in a solution based onthe total weight of the solution, i.e. to be calculated by the formula:(grams solute/grams solution)×100. This means that e.g. a compositioncomprising 21 g of EDTA in 79 g of water comprises 21 wt % of EDTA.

By “conditioning” is in the present context meant the cleaning of asurface, such as a mineralized surface or the surface of an implanthaving a metal containing surface, in order to remove e.g. biofilm,bacterial toxins, debris, bacteria, dental calculus (mineralizedbacterial deposits) and/or tissue remnants. Conditioning of a toothsurface also includes the removal of hydroxyapatite to expose collagenon the tooth root. “Conditioning” may thus be seen as a cleaning of asurface to remove unwanted substances therefrom and/or prepare thetreated surface in order to enable and/or support the regeneration ofthe surrounding tissue onto the conditioned surface. The conditioning ofa surface using the composition of the invention may also include anetching of said surface.

By “an implant having a metal containing surface” and the like is in thepresent context meant an implant whose surface in part or fully containsa metal material. For example approximately 10, 20, 30, 40, 50, 60, 70,80, 90 or 100% of the surface may be made of metal. The structureunderlying the implant surface may be made of a metal material oranother material, such as a ceramic or polyethylene. The metal materialmay e.g. be titanium or a titanium alloy, chromium or a chromium alloy,zirconium or a zirconium alloy, aluminium or an aluminium alloy,tantalum or stainless steel.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a comparison in contact angles obtained by treating atitanium disc surface with different compositions with and without EDTAand/or hydrogen peroxide.

DETAILED DESCRIPTION OF INVENTION

The present invention is directed to a composition comprisingethylenediaminetetraacetic acid (EDTA) at a concentration in the rangeof about 21-55% by weight and hydrogen peroxide (H₂O₂) at aconcentration of about 2-4% by weight. Such a composition isadvantageous for the conditioning of mineralized dental surfaces and/orsurfaces of a dental implant and/or increasing the hydrophilicity of animplant having a metal containing surface.

Suitable sources for EDTA include but are not limited to EDTA with oneor more acid groups carrying monovalent metal ions, such as, but notlimited to, Na⁺ or K⁺. Examples of such EDTA sources include, but arenot limited to disodium EDTA, tetrasodium EDTA and ethylenedinitriltetraacetic acid. Preferably the monovalent metal ion is Na⁺.

EDTA is an agent which chelates divalent cations, such as Ca²⁺, Mg²⁺,Fe²⁺ and Pb²⁺. It is widely used in infusion solutions fordetoxification and as an anticoagulant in vivo. In vitro it has avariety of uses such as to detach cells from solid substrats,decalcification of tissue specimens before sectioning and staining andas a detergent in biochemical analysis.

Etching of dentin or enamel is often performed as a surface treatment inconnection with bonding a composite resin to dentin or enamel with abonding agent or when binding a metal or orthodontic bracket to dentinor enamel of tooth. With conventional etching agents operating at a lowpH, such as pH 1, not only the mineral component of exposed dentinsurfaces is dissolved, but also the collagenous matrix. Collagen isdissolved at acid pH by acids such as citric acid already at weakconcentrations. In WO96/09029 it was demonstrated that EDTA etching incontrast to conventional etching agents will selectively removehydroxyapatite but not the collagenous matrix of dentin.

In addition to EDTA, a composition of the invention comprises hydrogenperoxide (H₂O₂) at a concentration of about 2-4% by weight. For example,the composition may comprise hydrogen peroxide at a concentration ofabout 2.5-3.5% by weight, such as e.g. 2.8-3.2% by weight. Theconcentration of hydrogen peroxide is preferably about 3% by weight.Among other effects, the hydrogen peroxide provides a disinfectingaction to the composition as well as it may aid in dissolving proteinsand/or removing biological debris. As explained later, a surprisingeffect that may be achieved by treating a metal containing surface witha composition comprising a combination of EDTA and hydrogen peroxide isan increased hydrophilicity of a metal containing implant surface.

In the present invention, hydrogen peroxide rather than a substancebeing able to give rise to hydrogen peroxide, such as perborate, isused. Perborate, for example, is not water soluble after the reactiongiving rise to hydrogen peroxide and a composition with perborate cantherefore be difficult to remove after use. In contrast, the compositionof the invention is easily removed after it has been allowed to act on asurface by applying a an e.g. an aqueous solvent or a physiologicalbuffer. Also, in the composition of the invention, hydrogen peroxide isdirectly available and ready to act on a surface. Thus the presentcomposition allows for short treatment times. The amount of hydrogenperoxide of the composition is high enough to provide for the desiredeffects, but still low enough to not deteriorate tissue surroundingdental mineralized tissues or dental implants. The hydrogen peroxide mayalso be provided by way of a peroxide or percarbonate salt, such assodium peroxide, potassium peroxide, calcium peroxide, magnesiumperoxide.

The range of the pH of a composition of the invention is typically about6-11.5. The composition of the invention may either have a pH aroundneutrality, such as about 6-8, or a basic pH such as a pH of about 8-11,such as 9-10, in particular about 9. In some aspects of the invention itmay be preferable to have a pH of about 9 or above.

The present inventors surprisingly found that by combining EDTA withhydrogen peroxide in a composition, it is possible to markedly increasethe hydrophilicity of an implant having a metal containing surface abovewhat may be achieved when EDTA or hydrogen peroxide are used alone (seeexperimental section). Thereby, a good hydrophilicity increasing effectmay be achieved even with a composition having a lower pH, such as a pHaround neutrality. The use of a pH around neutrality may e.g. beadvantageous as it decreases the risk that tissue not to be treated bythe composition of the invention is negatively affected by compositioncoming in contact with such tissue, e.g. by dropping or spilling.

The use of a more basic pH of the composition however provides otheradvantages to the composition. The present inventors have surprisinglyfound that it is possible to prepare a composition comprising a higherconcentration of dissolved EDTA by raising the pH of the composition. Byusing a higher pH of the composition it was found possible to dissolveEDTA above its normal saturation point in aqueous solutions, inparticular if a pH above 9 was used. One aspect of the invention istherefore directed to a composition having a pH of at least 9.0, such ase.g. about 9, 10 or 11. As a comparison, in the composition ofWO96/09029, due to the lower pH of that composition, not all of the EDTAadded is dissolved but some remains undissolved. As is demonstrated inthe experimental section the solubility of EDTA is greatly enhanced witha pH of 9. The composition is totally clear with a pH of 9. However, thecomposition is not completely clear at pH 8 and at pH 7. At pH 7, thesolubility of the EDTA is in the order of about 10-12%. Thus oneadvantage of the use of a higher pH is that EDTA is available in a muchhigher concentration to a surface to be treated with the composition.The combination of a high pH of the solution and the high concentrationmay be particularly advantageous to increase the hydrophilicity of atitanium surface. Also, by the use of a high pH, the negative effect onbone regeneration that may be caused by the use of conditioningcompositions having a low pH may be decreased.

As mentioned above, it may be desirable to use a pH that is not toobasic in order not to damage sensitive tissue. Thus, even if acomposition having a basic pH is desirable for use for a certainapplication, e.g. in order to have a composition having a higherconcentration of dissolved EDTA, it may be preferable to use a pH of9.0-10.0 as such a pH has a less risk of damaging surrounding tissuewhile still providing a high amount of dissolved EDTA.

The pH of the composition may e.g. be adjusted by the use of any base(i.e. a pH buffering agent) suitable for the intended use of thecomposition, such as ammonia and hydroxides of alkali metals andalkaline earth metals. Examples include, but are not limited to NaOH,KOH, LiOH, CsOH, RbOH and non-metallic bases such as triethanolamine(Trolamine), diethanolamine, ethanolamine, NH₃, phosphates such asNa₂HPO₄, Na₃PO₄, carbonates (Na₂CO₃), and bicarbonate (NaHCO₃).

The concentration of EDTA may e.g. be in the range of about 21-55% byweight, for example about 21-27, 21.6-26.4, 26-30, 30-35, 35-40 or40-50% by weight. For example, the concentration of EDTA may be about21.6, 22.0, 22.5, 23.0, 23.5, 24.0, 24.5, 25.0, 25.5, 26.0, 26.4, 27,28, 29, 30, 35, 40, 45, 50, or 55% by weight.

A composition of the invention having an amount of EDTA of about 21-27%by weight with a pH of about 9.0 or above enable a substantial part orall of the EDTA to be dissolved in the solution, thereby providing acomposition which contains no or little undissolved EDTA.

If the EDTA is provided at a higher concentration, such as e.g. about40-50% by weight, some EDTA remains undissolved. This undissolved EDTAmay provide an additional abrasive effect to the composition, inparticular when used in combination with a cleaning tool, such as thetool described in WO2009083281. For example, plaque may be more easilyremoved in this way. Such a composition having both a high concentrationof EDTA (e.g. 40-50% by weight) and a pH above 9 has both theadvantageous properties of a high amount of dissolved EDTA and anadditional amount of undissolved EDTA being able to provide an abrasiveeffect.

The present composition was found have advantageous effects when usedfor the conditioning of a mineralized dental surface and/or the surfaceof a dental implant. For example biofilm dissolution was increased. Alsoit was surprisingly found that the hydrophilicity of a metallic implantsurface was increased when the conditioning composition of the inventionwas used for conditioning of an implant surface due to the combinationof EDTA and hydrogen peroxide. A high hydrophilicity of an implantsurface is desirable e.g. as this has the effect of accelerating boneand soft tissue regrowth on and around the implant. Conditioning animplant surface with the composition of the invention may thus have theeffect of enabling and/or enhancing the osseointegration of the implant.Due to its advantageous effect of conditioning of mineralized surfacesand/or surfaces of an implant, the composition may also be denoted a“conditioning composition”.

A composition of the invention may also contain a viscosity increasingagent (viscosity modifier). The composition may thus e.g. take the formof a gel or a semi-fluid material. The use of such a viscosityincreasing agent allows a composition of the invention to be applied toa particular site and then essentially stay in place there. Thereby thecomposition is less likely to “spill”, or drip onto an undesiredsurface, for example a tissue not subject to the treatment, such as thetongue, gums or pallet. This may be advantageous as the composition ofthe invention is a powerful conditioning composition, which may harmsensitive tissue if not handled with care. By the use of a viscosityincreasing agent, it is possible to apply the composition in one placeand reduce the risk that the composition reaches surrounding tissue.

The amount of viscosity-increasing agent is typically maximally around15% by weight. It may be advantageous to use a lower concentration ofviscosity modifier in order to reduce the risk for negative interferenceof the viscosity modifier with the surface to be conditioned or theother constituents of the composition, such as the EDTA. Preferably theamount of viscosity modifier is about 1 to 5% by weight, e.g. 1-5,2.5-5.5, 3-5, 4-5% by weight. The amount of viscosity increasing agentmay thus be e.g. 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0.

The viscosity increasing agent may e.g. be selected from biocompatiblepolysaccharides, proteins, glycoproteins and synthetic polymers. Forexample, the viscosity increasing agent may be selected from cellulosesand derivatives and/or salts thereof, starches and derivatives and/orsalts thereof, plant gums, capsular microbial polysaccharides, and algalpolysaccharides. Suitable salts of these include any salt that ispharmaceutically acceptable, such as sodium salts.

Examples of suitable derivatives of cellulose include, but are notlimited to ethylcellulose, a water-insoluble commercial thermoplasticused in coatings, inks, binders, and controlled-release drug tablets;methylcellulose; hydroxypropyl cellulose; carboxymethyl cellulose;hydroxypropyl methyl cellulose, E464, commonly used as a viscositymodifier, gelling agent, foaming agent or binding agent; hydroxyethylmethyl cellulose, which is used in production of cellulose films.

Examples of derivatives of starch (modified starch) suitable for thepresent invention include, but are not limited to modified food starcheswhich are starches that has been chemically modified to allow the starchto function properly under conditions frequently encountered duringprocessing or storage, such as high heat, high shear, low pH,freeze/thaw and cooling.

A particularly interesting viscosity increasing agent for the purposesof the present invention is carboxymethylcellulose (CMC), or a saltthereof, such as the sodium salt of carboxymethylcellulose. CMC ispreferred as it is previously safely used in other medical devices, itis relatively heat resistant, pseudoplastic and available in differentmodifications and/or viscosity ranges.

The composition of the invention is preferably formulated as an aqueouscomposition, i.e. water is used as a solvent to dissolve the EDTA. Theamount of water in the composition is preferably at least 65% by weight,i.e. the water content of the composition is about 65-79 wt %, such asabout 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 or 79 wt %,in particular about 70-79 wt %, unless a concentration of EDTA of 35% byweight or more is used, in which case the amount of water naturally hasto be decreased. The water is preferably water for injection.

The composition of the invention may also consist of the EDTA andhydrogen peroxide in amounts as specified herein, optionally a pHbuffering agent to obtain the desired pH, an aqueous solvent andoptionally a viscosity increasing agent, wherein the composition has apH as specified herein. One example of such a composition is compositionconsisting of EDTA at a concentration in the range of about 21.6-26.4 byweight, hydrogen peroxide in a concentration of about 2-4% by weight, apH buffering agent in an amount so that the pH of the composition isabout 6-11.5, an aqueous solvent, and optionally a viscosity increasingagent, such as carboxymethylcellulose. Another example is a compositionconsisting of EDTA at a concentration in the range of about 21.6-26.4 byweight, hydrogen peroxide in a concentration of about 2-4% by weight, apH buffering agent in an amount so that the pH of the composition is pHof about 9.0-10.0, an aqueous solvent, and optionally a viscosityincreasing agent, such as carboxymethylcellulose. Yet another example isa composition consisting of EDTA at a concentration in the range ofabout 21.6-26.4 by weight, hydrogen peroxide in a concentration of about3% by weight, a pH buffering agent in an amount so that the pH of thecomposition is about 9.5, an aqueous solvent, and optionally a viscosityincreasing agent, such as carboxymethylcellulose. One example of acomposition of the invention having a higher amount of EDTA is acomposition consisting of EDTA in the range of about 40-50% by weight,hydrogen peroxide in a concentration of about 2-4% by weight, a pHbuffering agent in an amount so that the pH of the composition is about6-11.5, preferably about 9.5 or above, an aqueous solvent and aviscosity increasing agent. Examples of suitable pH buffering agents andviscosity increasing agents are described elsewhere herein.

Optionally, the composition of the invention does not contain any NaOCl.

The composition of the invention may be used for the conditioning of amineralized dental surface and/or a surface of a dental implant,preferably a dental implant having a metal containing surface. Theinvention therefore also is directed to the use of the composition forthe conditioning of a mineralized dental surface and/or a surface of adental implant. The conditioning may take place in situ in a subject,such as a human subject, or may take place ex situ, i.e. theconditioning takes place outside the body. The composition may thus beused for in situ conditioning and/or for ex situ conditioning. Oneaspect of the invention is thus directed to the use of the compositionfor the conditioning of a mineralized dental surface and/or a surface ofa dental implant, wherein said conditioning takes place ex situ. Forexample, an implant may be conditioned before implantation in a body. Animplant or a loose tooth may also be removed from the body, conditionedand then repositioned in the body.

Examples of mineralized dental surfaces which may be conditioned withthe composition of the invention include, but are not limited to, bonein the oral cavity, such as alveolar bone, and a tooth surface, such asa tooth root or a tooth root canal surface. Examples of mineralizeddental surfaces thus include dentin and enamel. A tooth is composed ofthe crown, which is the area covered in enamel above the cementoenameljunction and the root, which is found below the cementoenamel junctionand is covered with cementum. The crown is mainly composed of dentinwith the pulp chamber in the center. Dentin also composes most of theroot, which normally have pulp canals. A root canal is the space withinthe root of a tooth and contains the pulp chamber, the main canal(s),and more intricate anatomical branches that may connect the root canalsto each other or to the surface of the root. The pulp can be damagede.g. by decay, injury and/or gum disease. Such damage may lead to aninfection in the tooth causing blood vessels and nerves to die,eventually leaving the tooth “dead”. Root canal treatment may be used toremove damaged pulp and infections bacteria. The empty root canal systemis then cleaned, filled and a permanent seal is put over the top of thetooth. In order for such a root filling to be successful, it isimportant that the dead and/or infected tissue, including any bacteria,is efficiently removed before filling the root canal. The composition ofthe invention is very suitable for such treatment of root canals and themineralized dental surface to be conditioned with a composition of theinvention may thus be a root canal surface.

Implant surfaces to be conditioned with a composition of the inventionmay be any kind of implant surfaces, such as the surface of a metallic,ceramic or plastic implant. The composition of the invention isparticularly suitable for the conditioning of dental implants having ametal containing surface. In different embodiments of the invention, thesurface conditioned is thus the surface of a dental implant having ametal containing surface. As explained above, not the entire surface ofthe implant or the entire underlying structure has to be made of metal,but any metal containing parts of the surface may benefit from theconditioning by use of the composition of the invention. Theconditioning may either be performed in situ i.e. when the implant is inplace in a body or it may be performed before implantation.Alternatively, an implant (e.g. a crown) may be removed from a body,cleaned and repositioned in a body, i.e. the conditioning takes place exsitu. The conditioning of an implant having a metal containing surfaceusing the composition of the invention has, in addition to the cleaningactivity of the composition removing unwanted substances (such asbiofilm) as explained later, the additional advantage of improving thehydrophilicity of the implant. A high hydrophilicity of an implantsurface is desirable e.g. as this has the effect of accelerating boneand soft tissue regrowth on and around the implant. The composition ofthe invention may thus also be used to improve the hydrophilicity of animplant, before implantation of a new implant and/or during the cleaning(conditioning) of an implant removed from a body before itsrepositioning therein. One aspect of the invention is therefore directedto the use of a composition of the invention for improving thehydrophilicity of a dental implant, such as a dental implant having ametal containing surface.

Restorative materials which benefit from conditioning by the compositionof the invention include those known in the art. Composite materials,synthetic bone materials, bone-like apatite and hydroxyapatite materialsare well suited for use with the compositions and methods of theinvention. Suitable examples of dental restoratives include compositefilling materials, inlays, onlays, crown, bridges, ceramics, veneers andMaryland bridges. As mentioned above, the composition of the inventionmay also be used to prepare a clean mineralized surface before theapplication of a restorative material thereto.

The effective removal of biofilm, bacterial toxins, debris, bacteria,dental calculus (mineralized bacterial deposits) and/or tissue remnantsby the conditioning effect of the composition of the invention hasnumerous advantages. Also, the composition of the invention may removecalcium ions. This is particularly advantageous in the case of plaquewhich sometimes contains ions such as calcium. Plaque may be difficultto remove by mechanical cleaning only. However, by removing calciumions, the plaque disintegrates and may be removed with the conditioningcomposition. The conditioning composition according to the presentinvention leaves a “clean” surface which facilitates attachment andre-growth of soft tissue to the mineralized surface or the implant. Forexample, tooth attachment may be improved by conditioning of a toothroot surface using the composition of the invention. In addition, thecomposition of the invention may be used for root canal conditioninge.g. in order to remove pulp tissue. The conditioning also leads to areduced risk for inflammation and/or infection as e.g. bacteria,bacterial toxin and/or infected/necrotised tissue is removed from themineralized surface and/or implant surface. In addition, theconditioning of a mineralized surface and/or implant surface using thecomposition of the invention also has the effect of increasing thehydrophilicity of the surface. This may also lead to accelerated boneand soft tissue re-growth. In addition, the conditioning of a surfacewith the composition of the invention may improve the bonding ofrestorative dental materials such as amalgams, composites, resins andcementitious materials. The composition of the invention may thereforebe used for one or more of the above stated purposes. What is more, thecomposition of the invention is non-toxic.

The composition of the invention is particularly useful for theprevention and/or treatment of different disease and/or conditions inthe oral cavity. Examples of such conditions include, but are notlimited to, periodontal disease, periimplantitis, caries and/or aninfection and/or inflammation in the root canal. The invention is thusalso directed to the conditioning composition for use as a medicament.The invention is in addition directed to the conditioning compositionfor use in the prevention and/or treatment of a periodontal disease,periimplantitis, caries and/or an infection and/or inflammation in theroot canal. Such a prevention and/or treatment comprises theconditioning of a mineralized dental surface and/or the surface of adental implant with the composition of the invention. In such aprevention and/or treatment the mineralized surface and/or the implantsurface may benefit from the prevention and/or treatment, but alsosurrounding soft tissue may benefit, as the removal of infectiousbacteria, toxins, necrotized tissue etc. also e.g. may cause a softtissue inflammation and/or infection to heal. For example, in theprevention and/or treatment of periodontal disease one or more of theaffected tissues, including the gums, periodontal ligament, cementum,and alveolar bone may react positively to the prevention and/ortreatment.

Periimplantitis is an inflammation in and around the area of a dentalimplant that may also affect abutment areas. By the use of thecomposition of the invention for the conditioning of the surfaces of adental implant, and/or the bone to which the implant is attached, thetreatment outcome of the perimplantitis may be improved as e.g.infectious material and/or necrotized tissue may be removed by using acomposition of the invention. Also, conditioning of an implant surfacewith the composition of the invention may enable and/or enhance theosseointegration of the implant. The composition of the invention maytherefore be used for enhancing and/or enabling the osseointegration ofan implant. The invention is thereby also directed to a method forenabling and/or enhancing the osseointegration of an implant comprisingtreating the implant with a conditioning composition of the invention.The composition of the invention is particularly interesting for use inthe prevention and/or treatment of periimplantitis.

As mentioned above, the composition of the invention may also bebeneficial in the case of an infection and/or inflammation in a rootcanal. Pulpitis is an example of an inflammation in the root canal thatmay be caused by dental caries. Pulpitis causes increased sensitivity tostimuli, such as heat and cold. In such a prevention and/or treatment ofan infection and/or inflammation in a root canal, dead and/or infectedtissue, including any bacteria, is removed by conditioning with thecomposition as defined herein, optionally in combination with mechanicalcleaning of the root canal.

Another embodiment the invention resides in a composition for use intooth root conditioning by selective removal of an exposed tooth rootsurface so as to improve subsequent attachment of the tooth inconjunction with periodontal surgery.

The invention is also directed to the use of a composition as definedherein for the preparation of a medicament for the prevention and/ortreatment of a periodontal disease, periimplantitis, caries and/or aninfection and/or inflammation in the root canal. The invention is alsodirected to a method for preventing and/or treating a periodontaldisease, periimplantitis, caries and/or an infection and/or inflammationin the root canal comprising the administration of a therapeuticallyeffective amount of a composition as defined herein to a subject, suchas a mammal, in need thereof. Such prevention and/or treatment comprisesthe conditioning of a mineralized dental surface and/or the surface of adental implant with the composition of the invention. The composition ofthe invention is particularly interesting in connection with theprevention and/or treatment of periimplantitis.

The invention also encompasses a method for the conditioning of amineralized dental surface and/or a surface of a dental implantcomprising treating the surface with an effective amount of theconditioning composition.

When the composition of the invention is used to condition a surface,such a method for conditioning comprises the steps of applying thecomposition to the surface to be treated, allowing the composition toact for a suitable time period, and thereafter removing the compositionfrom the surface, preferably by rinsing with water or a physiologicalsalt buffer. After application of the composition to the surface to beconditioned in a manner suitable depending on the specific surface, thecomposition is allowed to act for a time period of typically a fewminutes, such as 1, 2, 3, 4, 5, 6, 7 or 8 minutes. Preferably, thecomposition is applied for 5 min or less. Even if the composition of theinvention is a powerful conditioning agent, the composition is mainlyapplied to a “dead” surface or a surface where without treatment nothingwould grow. Thereby the risk that tissue is negatively affected by thecomposition is reduced. Also, the viscosity increasing agent thatpreferably is added to the composition allows for the composition to beapplied to and basically stay at its site of application, thereby alsoreducing the risk for negative effects on tissue. After being allowed toact on a surface, the composition is removed from the surface, e.g. byrinsing with sterile water or a physiological buffer, such as 0.9% NaCl.The rinsing is preferably performed until no more of the conditioningcomposition is visible on the surface. The composition may be applied bythe use of any device suitable for the specific surface the compositionis to be applied to. One example of such a device is a syringe, whichmay be used e.g. in the case of application to a root canal surface orother narrow or confined space. The composition may also be applied to asponge, compress and the like, which then is used to clean the surface.Alternatively, the composition may be used in conjunction with differentcleaning devices such as conventional brushes intended for the cleaningof a mineralized surface and/or implant surface. The invention thus isalso directed to a kit comprising a vial with the conditioningcomposition and a device for the application to, and/or a device forcleaning, a mineralized dental surface and/or a surface of a dentalimplant. One example of such device is the device disclosed inWO2009083281. Alternatively, the composition may be provided directly ina device intended for application of the composition to a surface. Sucha device may also be intended for storage of the composition before use.The kit may also comprise instructions for the cleaning of surfacesusing the kit of the invention and/or solutions, such as water or aphysiological salt buffer, for removing the composition of the inventionfrom the surface it has been applied to.

The composition of the invention is prepared by dissolving an amount ofEDTA in water so that the final concentration is as defined herein andadjusting the pH with a suitable base (i.e. a pH buffering agent) to thedesirable pH (if necessary). Hydrogen peroxide is added to thecomposition either before, simultaneously or after the addition of EDTA.The method for preparing the composition of the invention may alsocomprise the step of adding a viscosity increasing agent as definedherein to the composition to provide a final concentration as definedherein, either before, after or simultaneously with the addition of thehydrogen peroxide and the EDTA. The pH of the composition may beadjusted before or after the addition of the EDTA, the hydrogen peroxideand the optionally added viscosity increasing agent.

EXPERIMENTAL SECTION Example 1

2.75 g CMC (Blanose) was slowly added to 70 g of water for injection. Toavoid lumping, the water is heavily stirred.

After adding all CMC, the solution was heated up to 80° C. and thesolution is stirred for an additional 20 min (max.) CMC should now becompletely dissolved. The solution was cooled down to ca. 50° C. and 24g of EDTA was slowly added to the solution. The pH was adjusted with 5 MNaOH to reach approximately pH 7. After 1 h, the solution was adjustedto 100 g. After additional 30 min of stirring, the solution was steamsterilized for 20 min at 121° C. After steam sterilization, the solutionis stirred during the cool down phase.

Example 2

The 6.03 g of the solution (example 1) was taken and the pH was adjustedwith 92.5 mg NaOH (100%). The pH was 8. Another solution was preparedwith 5.98 g and the addition of 188.6 mg NaOH (100%). The pH of thissolution was 9. To each of the solution approximately 3% wt hydrogenperoxide was added. For example solution 1: To 2.95 g, 265 μl ofconcentrated hydrogen peroxide was added.

The appearance of all three solutions was different:

Solution 1 (pH 7): opaqueSolution 2 (pH 8): slightly opaqueSolution 3 (pH 9): transparent

Example 3

The three solutions from example 2 were applied onto sand blasted andacid etched titanium discs. Approximately 0.6 ml of the solution wasapplied on 3 discs each. After 2 mins, the solution was washed away withpurified water. Until the measurement, the discs were kept in purifiedwater. Prior to the determination of the contact angle, the samples weredried with argon. The contact angle was determined once per disc. Thefollowing values were found:

TABLE 1 contact angle of titanium discs after treatment with differentEDTA + hydrogen peroxide containing compositions Treatment Contact angleTitanium disc treated with EDTA-H₂O₂ solution (pH 7) 72.6 Titanium disctreated with EDTA-H₂O₂ solution (pH 8) 5.5 Titanium disc treated withEDTA-H₂O₂ solution (pH 9) 0.0

Example 4

As a control, solutions without EDTA were prepared, containing only 3weight-% H₂O₂ and CMC.

TABLE 2 contact angle of titanium discs after treatment with differenthydrogen peroxide containing compositions Treatment Contact angleTitanium disc treated with H₂O₂ solution (pH 7) 80.7 Titanium disctreated with H₂O₂ solution (pH 8) 60.0 Titanium disc treated with H₂O₂solution (pH 9) 13.7

Example 5

In addition, control solutions containing only EDTA but no hydrogenperoxide were prepared. 2.75 g CMC (Blanose) was slowly added to 70 g ofwater for injection. To avoid lumping, the water was heavily stirred.After adding all CMC, the solution was heated up to 80° C. and thesolution was stirred for an additional 20 min (max.) CMC is nowcompletely dissolved. The solution was cooled down to ca. 50° C. and 24g of EDTA was slowly added to the solution. The pH was adjusted with 5 MNaOH to reach approximately pH 7. After 1 h, the solution was adjustedto 100 g. After additional 30 min of stirring, the solution was steamsterilized for 20 min at 121° C. After steam sterilization, the solutionwas stirred during the cool down phase. The 6.03 g of the solution wastaken and the pH was adjusted with 92.5 mg NaOH (100%). The pH was 8.Another solution was prepared with 5.98 g and the addition of 188.6 mgNaOH (100%). The pH of this solution was 9.

The appearance of all three solutions was different:

Solution 1 (pH 7): opaqueSolution 2 (pH 8): slightly opaqueSolution 3 (pH 9): transparent

The three solutions were applied onto sand blasted and acid etchedtitanium discs. Approximately 0.6 ml of the solutions were applied on 3discs each. After 2 mins, the solution was washed away with purifiedwater. Until the measurement, the discs were kept in purified water.Prior to the determination of the contact angle, the samples were driedwith argon. The contact angle was determined once per disc and thefollowing values were found:

TABLE 3 contact angles of titanium discs after treatment with EDTAcompositions with different pH. Treatment Contact angle Titanium discuntreated 122 Titanium disc treated with EDTA solution (pH 7) 72Titanium disc treated with EDTA solution (pH 8) 85 Titanium disc treatedwith EDTA solution (pH 9) 41

Conclusion Examples 3-5

The lower the contact angle of a surface is, the higher thehydrophilicity of the surface is. As can be seen, when a surface istreated with a composition having both EDTA and hydrogen peroxide, thecontact angle is decrease compared to when hydrogen peroxide or EDTA areused alone. In FIG. 1 the different solutions of Examples 3-5 arecompared to each other.

The use of a composition comprising both EDTA and hydrogen peroxidetherefore has the effect of increasing the hydrophilicity of thesurface. The composition of the invention therefore also has an improvedconditioning effect.

Example 6

In another experiment, treatment with an EDTA solution containinghydrogen peroxide at pH 10 was compared to treatment with an EDTAsolution with pH 7.

The treated titanium discs (according example 3), were analysed withXPS. The following normalized atomic concentration for carbon was found:

TABLE 4 carbon content on titanium surface after treatment withdifferent compositions with and without EDTA and/or hydrogen peroxide.Treatment Carbon content Titanium disc untreated 18% Titanium disctreated with EDTA solution (pH 7) 21% Titanium disc treated withEDTA-H₂O₂ solution (pH 10)  8%

Basically all surfaces are contaminated with carbon and removal ofcarbon from a surface may therefore be used to demonstrate a cleaningeffect of a composition. As can be seen, by conditioning the titaniumsurface with a composition comprising both EDTA and hydrogen peroxide atpH 10, a markedly higher amount of carbon could be removed from thesurface than when EDTA at pH 7 was use alone, thereby demonstrating thegood conditioning (cleaning) effect of the composition of the invention.

1. A conditioning composition comprising ethylenediaminetetraacetic acid(EDTA) at a concentration in the range of 21-55% by weight and hydrogenperoxide (H₂O₂) at a concentration of 2-4% by weight.
 2. A conditioningcomposition according to claim 1, wherein the concentration of EDTA isin the range of 21-27% by weight.
 3. A conditioning compositionaccording to claim 1, wherein the concentration of EDTA is in the rangeof 21.6-26.4 by weight.
 4. A conditioning composition according to claim1, wherein the concentration of hydrogen peroxide is about 3% by weight.5. A conditioning composition according to claim 1, wherein the pH ofthe composition is in the range of 6-11.5.
 6. A conditioning compositionaccording to claim 1, wherein the pH of the composition is 9.0 or above.7. A conditioning composition according to claim 1, further comprising aviscosity increasing agent.
 8. A conditioning composition according toclaim 7, wherein the viscosity increasing agent is selected from thegroup consisting of polysaccharides, proteins, glycoproteins andsynthetic polymers.
 9. A conditioning composition according to claim 7,wherein said viscosity increasing agent is carboxymethylcellulose, or asalt thereof.
 10. A conditioning composition consisting essentially ofEDTA at a concentration in the range of 21-55% by weight, hydrogenperoxide at a concentration of 2-4% by weight, and an aqueous solvent.11. A conditioning composition consisting essentially of EDTA at aconcentration in the range of 21-55% by weight, hydrogen peroxide at aconcentration of 2-4% by weight, an aqueous solvent and a pH bufferingagent.
 12. A conditioning composition consisting essentially of EDTA ata concentration in the range of 21-55% by weight, hydrogen peroxide at aconcentration of 2-4% by weight, an aqueous solvent and a viscosityincreasing agent.
 13. A conditioning composition consisting essentiallyof EDTA at a concentration in the range of 21-55% by weight, hydrogenperoxide at a concentration of 2-4% by weight, an aqueous solvent, a pHbuffering agent and a viscosity increasing agent.
 14. A conditioningcomposition according to claim 1, wherein the composition is amedicament.
 15. A method for preventing and/or treating a periodontaldisease, periimplantitis, caries and/or an infection and/or inflammationin the root canal comprising the administration of a therapeuticallyeffective amount of the composition according to claim 1 to a subject,in need thereof.
 16. A method according to claim 15, wherein said methodcomprises the conditioning of a mineralized dental surface and/or thesurface of a dental implant with the conditioning composition accordingto claim
 1. 17. A method for conditioning a mineralized dental surfaceand/or a surface of a dental implant comprising treating the surfacewith an effective amount of the conditioning composition according toclaim
 1. 18. A method for enabling and/or enhancing osseointegration ofan implant comprising treating the implant with the conditioningcomposition according to claim
 1. 19. A kit comprising a vial with theconditioning composition according to claim 1 and a device for theapplication to, and/or a device for cleaning, a mineralized dentalsurface and/or a surface of a dental implant.
 20. A method according toclaim 15, wherein the subject is a mammal.